Cancer in children, adolescents, and young adults is an orphan disease. The prevalence of non-CNS solid tumors in this age group is ~90,000; the prevalence of those who are not cured by current therapies is ~27,000. Cure rates for patients with multiply relapsed or metastatic non-CNS solid tumors, particularly sarcomas, remain <30% despite aggressive multimodal therapy including surgery, radiation, and chemotherapy. The applicant's preliminary data suggest the highly malignant types of cancers commonly found in children, adolescents, and young adults in human xenograft models are susceptible to killing by attenuated herpes simplex virus mutants. HSV1716 is an ICP34.5 mutant under development by Crusade Laboratories, Ltd. These oncolytic mutant viruses are lytic for many types of cancer cells, but are attenuated in their ability to replicate in normal cells. The mechanisms of cytotoxicity induced by these agents circumvent traditional cancer-resistance mechanisms. HSV1716 has been shown to be safe in several previous clinical trials by Crusade via intratumoral injection in adults with brain tumors, head/neck squamous cell carcinomas, and melanomas, but has not been tested for safety in young patients or for injection into non-CNS, deep-seated tumors. The applicant hypothesizes that intratumoral injection of HSV1716 is safe in young patients with tumors in superficial regions (extremities, head and neck) as well as retroperitoneal and lung locations, with minimal shedding of virus. Based on their preclinical efficacy studies, the applicant proposes a Phase 1 clinical trial to test the safety of direct intratumoral injections of HSV1716 in adolescents and young adults with relapsed or refractory non-CNS solid tumors. They will test their hypothesis in two specific aims: (1) Assess the safety and feasibility of single and repeated intratumoral HSV1716 administration in adolescents and young adults with relapsed cancer, and (2) Determine the incidence of HSV1716 virus spread following intratumoral virus injection. This study will be the first clinical step in developing HSV1716 as a new method of local control for non-CNS solid tumors, to be used when surgery and radiotherapy are not options or no longer effective. The project is the first step in ultimately gaining FDA approval for HSV1716 for these patients. Because nonclinical data suggest systemic delivery of the virus may also have therapeutic benefit for metastases, this study may also enable future trials of systemic HSV1716.